ALPHA ACTININ 4: AN INTERGRAL COMPONENT OF TRANSCRIPTIONAL PROGRAM REGULATED BY NUCLEAR HORMONE RECEPTORS
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Case Western Reserve University School of Graduate Studies / OhioLINK
2011
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ndltd-OhioLink-oai-etd.ohiolink.edu-case13100579092021-08-03T05:34:10Z ALPHA ACTININ 4: AN INTERGRAL COMPONENT OF TRANSCRIPTIONAL PROGRAM REGULATED BY NUCLEAR HORMONE RECEPTORS Khurana, Simran Biochemistry <p>Overexpression and mutations of the actin-binding protein alpha actinin 4 (ACTN4) are linked to tumorigenesis. However, the mechanisms by which ACTN4 links to oncogenesis are not completely understood. The role of ACTN4 protein in maintaining cytoskeletal integrity is well known yet little is known about the nuclear function of ACTN4. Our study dissects a novel role of ACTN4 in nuclear receptor-mediated transcriptional regulation. Our results demonstrate that ACTN4 potentiates transcriptional activity of the estrogen receptor by antagonizing and displacing histone deacetylase 7 (HDAC7) from the selected estrogen receptor (ERα) target genes. Furthermore, we show here that ACTN4 plays an important role in the proliferation of MCF-7 breast cancer cells by transcriptionally regulating selected estrogen receptor target genes. </p><p>In humans, another important phenotype associated with ACTN4 mutations (K228E, T232I and S235P) is linked to a kidney disease known as familial focal segmental glomeruscleorsis (FSGS), characterized by proteinuria and effacement of podocytes (highly differentiated kidney cells). Despite the intense investigation the role of ACTN4 in normal podocyte development as well as the role of ACTN4 mutations in disease pathogenesis is not well understood. Here we have shown a mechanism by which ACTN4 mutants might contribute to the disease. We demonstrate that FSGS-linked ACTN4 mutants are defective in regulating the transcription mediated by nuclear receptors due to their aberrant localization and defect in their ability to interact with nuclear hormone receptors including glucocorticoid receptor (GRα) and retinoic acid receptor (RARα). In summary, our work identifies a previously unknown function of ACTN4 in nuclear receptor mediated transcription. Our results have implications for understanding the role of ACTN4 in the pathophysiology of oncogenesis and FSGS.</p> 2011 English text Case Western Reserve University School of Graduate Studies / OhioLINK http://rave.ohiolink.edu/etdc/view?acc_num=case1310057909 http://rave.ohiolink.edu/etdc/view?acc_num=case1310057909 unrestricted This thesis or dissertation is protected by copyright: all rights reserved. It may not be copied or redistributed beyond the terms of applicable copyright laws. |
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NDLTD |
| language |
English |
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NDLTD |
| topic |
Biochemistry |
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Biochemistry Khurana, Simran ALPHA ACTININ 4: AN INTERGRAL COMPONENT OF TRANSCRIPTIONAL PROGRAM REGULATED BY NUCLEAR HORMONE RECEPTORS |
| author |
Khurana, Simran |
| author_facet |
Khurana, Simran |
| author_sort |
Khurana, Simran |
| title |
ALPHA ACTININ 4: AN INTERGRAL COMPONENT OF TRANSCRIPTIONAL PROGRAM REGULATED BY NUCLEAR HORMONE RECEPTORS |
| title_short |
ALPHA ACTININ 4: AN INTERGRAL COMPONENT OF TRANSCRIPTIONAL PROGRAM REGULATED BY NUCLEAR HORMONE RECEPTORS |
| title_full |
ALPHA ACTININ 4: AN INTERGRAL COMPONENT OF TRANSCRIPTIONAL PROGRAM REGULATED BY NUCLEAR HORMONE RECEPTORS |
| title_fullStr |
ALPHA ACTININ 4: AN INTERGRAL COMPONENT OF TRANSCRIPTIONAL PROGRAM REGULATED BY NUCLEAR HORMONE RECEPTORS |
| title_full_unstemmed |
ALPHA ACTININ 4: AN INTERGRAL COMPONENT OF TRANSCRIPTIONAL PROGRAM REGULATED BY NUCLEAR HORMONE RECEPTORS |
| title_sort |
alpha actinin 4: an intergral component of transcriptional program regulated by nuclear hormone receptors |
| publisher |
Case Western Reserve University School of Graduate Studies / OhioLINK |
| publishDate |
2011 |
| url |
http://rave.ohiolink.edu/etdc/view?acc_num=case1310057909 |
| work_keys_str_mv |
AT khuranasimran alphaactinin4anintergralcomponentoftranscriptionalprogramregulatedbynuclearhormonereceptors |
| _version_ |
1719421868788678656 |